Gaining Mechanistic Insight Into Coproporphyrin I as Endogenous Biomarker for OATP1B-Mediated Drug-Drug Interactions Using Population Pharmacokinetic Modeling and Simulation
Gaining Mechanistic Insight Into Coproporphyrin I as Endogenous Biomarker for OATP1B-Mediated Drug-Drug Interactions Using Population Pharmacokinetic Modeling and Simulation
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DOI：
10.1002/cpt.983
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发表时间：
2018-09-01
影响因子：
6.7
通讯作者：
Galetin, Aleksandra
中科院分区：
文献类型：
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作者：
Barnett, Shelby;Ogungbenro, Kayode;Galetin, Aleksandra
本研究使用非线性混合效应模型评价了粪卟啉I（CPI）作为OATP 1B介导的药物相互作用（DDI）相对于临床探针瑞舒伐他汀的选择性内源性生物标志物。对存在/不存在利福平时的血浆和尿液CPI数据进行建模，以描述CPI合成、消除清除率，并获得利福平体内OATP Ki。该生物标志物显示稳定的病例间基线浓度和较低的个体间变异性（85%）。使用CPI数据估计的利福平体内未结合OATP Ki（0.13 M）比瑞舒伐他汀低2倍。基于模型的模拟和把握度计算证实了CPI在充分把握度的临床研究中识别中度和弱OATP 1B抑制剂的灵敏度。当前分析提供了CPI作为内源性OATP 1B生物标志物的最详细评价，以支持最佳DDI研究设计;需要一组抑制剂的进一步药物基因组学和DDI数据。
This study evaluated coproporphyrin I (CPI) as a selective endogenous biomarker of OATP1B-mediated drug-drug interactions (DDIs) relative to clinical probe rosuvastatin using nonlinear mixed-effect modeling. Plasma and urine CPI data in the presence/absence of rifampicin were modeled to describe CPI synthesis, elimination clearances, and obtain rifampicin in vivo OATP Ki. The biomarker showed stable interoccasion baseline concentrations and low interindividual variability (85%). Estimated rifampicin in vivo unbound OATP Ki (0.13 M) using CPI data was 2-fold lower relative to rosuvastatin. Model-based simulations and power calculations confirmed sensitivity of CPI to identify moderate and weak OATP1B inhibitors in an adequately powered clinical study. Current analysis provides the most detailed evaluation of CPI as an endogenous OATP1B biomarker to support optimal DDI study design; further pharmacogenomic and DDI data with a panel of inhibitors are required.